Chiral adsorbents and preparation thereof as well as compounds on which the adsorbents are based and preparation of these compounds

ABSTRACT

Optically active adsorbents based on network polymerized derivatives of dicarboxylic acids, diamines or diols which are chemically bonded to a carrier. The derivatives can be polymerized by radical polymerization or through hydrosilylation in the presence of a solid carrier. The optically active adsorbents are usable for chromatographic separation of racemic mixtures of enantiomers.

The present invention relates to new chiral adsorbents and to methodsfor preparing them. The invention also relates to certain new compoundson which the chiral adsorbents are based and to the preparation of thesenew compounds.

Optical isomers can be separated by the formation of diastereomers usingchiral reagents, followed by separation using liquid or gaschromatography or crystallisation, or by direct chromatographicseparation using chiral phase systems. The growing interest in resolvingpharmaceutical substances and determining their enantiomeric purity hasentailed an increased need of direct chromatographic separation OFENANTIOMERS. This separation technique uses either a chiral selectivesubstance in the mobile phase or a chiral stationary phase. In recentyears, great attention has been paid to direct chromatographicseparation of enantiomers using chiral stationary phases. A number ofdifferent chiral adsorbents have been suggested, but only a few of them,such as those based on cellulose derivatives or derivatised amino acids,have met with any appreciable commercial success in preparativechromatography. This largely depends on the stringent demands that areplaced on chiral stationary phases to be suitable for preparative, i.e.large-scale, separations, primarily by HPLC (High Performance LiquidChromatography). For such separations, the columns must have highenantioselectivity, high capacity, i.e. allowing the addition ofrelatively large amounts of racemate, high efficiency, i.e. giving smallband broadening in the chromatogram, as well as high universality, i.e.allowing separation of as many structurally different types of chemicalcompounds as possible.

According to the present invention, chiral stationary phases based onnetwork polymerised derivatives of dicarboxylic acids, diamines, diolesor hydroxy acids which are chemically bonded to a solid carrier havebeen found to thoroughly satisfy the demands placed on such phases foruse in both analytical and preparative separations. One example of suchan derivative is tartaric acid as such which is one of the lessexpensive optically active organic starting materials available on themarket today, which makes the present invention in its different aspectseconomically attractive.

The optically active adsorbent according to the invention ischaracterized in an optically active network polymer covalently bound toa carrier.

The optically active network polymer comprises optically activederivatives of dicarboxylic acids, diamines, dioles or hydroxy acids.

Each functional group of the optically active derivatives ofdicarboxylic acids, diamines or dioles comprises at least one aliphaticcarbon residue with up to 15 carbon atoms and at least one terminalunsaturation.

Derivatives of diols are aliphatic esters, carbonates or carbamateshaving up to 15 carbon atoms in the carbon chain and a terminalunsaturation.

Derivatives of diamines are amides, carbamates and urea having up to 15carbon atoms in the carbon chain and a terminal unsaturation.

Derivatives of the dicarboxylic acids are esters and amides having up to15 carbon atoms in the carbon chain and a terminal unsaturation.

The most preferred derivative of the hydroxy acids is tartaric acid.

Examples of compounds of interest are:

D- or L-tartaric acid

(1R,2R)-(−)-1,2 diamino cyclohexan

(+)-2.2′-diamino binaphthyl -(1,1′)

(1R,2R)-(−)-1,2-cyclohexan diol

(+)-(2R,3R)-1,45-dimethoxy-2,3-butandiol

D-(−)-citramalic acid

D-(+)-malic acid.

The invention is defined in more detail in the appended claims.

The adsorbents are according to one preferred embodiment of the presentinvention based on network polymerised tartaric acid derivatives whichare bonded to a carrier, such as a silica gel (SiO₂ gel). As is known inthe art, certain tartaric acid derivatives bonded to silica gel can beused as chiral stationary phases. Such phases with non-polymericderivatives bonded to silica (so-called brush type) as well as a numberof chiral applications for such tartaric acid derivatives, are describedby W. Lindner and I. Hirschböck in J. Pharm. Biomed. Anal. 1984, 2, 2,183-189. Chiral stationary phases based on a simple, non-polymerictartaric acid derivative are also disclosed by Y. Dobashi and S. Hara inJ. Org. Chem. 1987, 52, 2490-2496. The advantages of the tartaric acidderivative being part of a network polymer phase, as in the presentinvention, are that several chiral centres are obtained on the carrier,which results in increased capacity, and that a more protected carriersurface is obtained. For a silica carrier, this results in a reducednumber of accessible free silanol groups, which means a decrease ofachiral polar interactions, which impair the enantioselectivity.Enhanced enantioselectivity is also obtained with a polymer phase ascompared with a monomer one, probably because the polymer can form athree-dimensional structure that can have chiral cavities.

The tartaric acid derivatives that are polymerised are in themselvesoptically homochiral derivatives and contain at least two stereogeniccentres. The derivatives can be characterised by the general formula:

wherein R₁ is a group RNH—, RO—, RR′N— or HO— and R₂ is a group RNHCO—,RCO—, ROCO—, H— or R—, R being an aliphatic hydrocarbon residue havingup to 15 carbon atoms, an aryl group, an aralkyl group, naphthyl groupor an anthryl group and R′ being hydrogen or an alkyl group having up to7 carbon atoms, the derivatives containing at least two groups R₁ or R₂containing an aliphatic unsaturation. R₁ and R₂ may contain one or morechiral centres. When R is an aliphatic hydrocarbon residue, this may bean alkyl, a cycloalkyl, an alkenyl or an alkynyl group. R then suitablycontains up to 10 carbon atoms and suitably is an alkyl or alkenyl groupand preferably an alkenyl group. R may be an aryl group or an aralkylgroup. These groups may contain 1, 2 or 3 rings and be unsubstituted orsubstituted with one or more substituents on the ring or rings. Examplesof such substituents are alkyl groups, hydroxy groups, halogens, nitrogroups and alkenyl groups. R′ suitably is hydrogen or an alkyl grouphaving 1 or 2 carbon atoms. Suitably, R₁ is a group RNH—, RO— or RR′N—,and preferably a group RNH—. R then suitably is an allyl group, analpha-phenylethyl group or a naphthyl group and most preferred any ofthe two first-mentioned ones. R₂ suitably is a group RNHCO—, RCO— or H—and preferably a group RNHCO— or RCO—. R then suitably is a phenyl, anallyl, a 3,5-dinitrophenyl, an naphthyl, a methacryl, analpha-phenylethyl, a 3,5-dimethylphenyl, a tertiary-butyl, or anisopropyl group. Preferably, R is a phenyl, an allyl, a3,5-dinitrophenyl, an naphthyl, a methacryl or an alpha-phenylethylgroup. The two groups R₁ in the derivatives should be equal, and the twogroups R₂ should also be equal.

Especially suitable are tartaric acid derivatives of formula I which canbe characterised by the formulae

In compounds of formula Ia, R₁ thus is an allyl amine residue, and incompounds of formula Ib, R₁ is a phenylethyl amine residue and R₂ is asdefined above.

Compounds of formula Ia include diallyl tartaric diamide (R,R or S,S)which is commercially available, and derivatives thereof. In compoundsof formula Ia, R₂ suitably is a group RNHCO—, RCO— or H, R being asdefined above. R may, for example, be a bulky alkyl group, such asisopropyl or tertiary butyl, a benzyl group, a phenyl group, a naphthylgroup or an anthryl group, and any substituents on the aromatic ring maybe any of those indicated above. Most preferred, R₂ is a group RNHCO— orRCO—, where R contains an aryl group, which optionally is substituted.Advantageously, the compounds contain an aromatic nucleus, sinceπ,π-interactions are then obtained with aromatic racemates, which mayconfer advantages in separation. Examples of some specific, suitablegroups R₂ for compounds of formula Ia are: phenyl carbamoyl,α-phenylethyl carbamoyl, 3,5-dimethylphenyl carbamoyl, naphthylcarbamoyl, α-naphthylethyl carbamoyl, benzoyl, and 3,5-dinitrobenzoyl,and 3,5-dimethylbenzoyl.

Compounds of formula Ia can be prepared by conventional acylation andcarbamoylation reactions. Esters of diallyl tartaric diamide can thus beprepared by reacting the diamide with the corresponding acid chloride oracid anhydride. Suitably, the diamide is dissolved in a solvent whichalso acts as a base, e.g. pyridine, whereupon the corresponding acidchloride is added, suitably in an at least equimolar amount. Aftercompletion of the reaction, which may be conducted at room temperature,the resulting product is processed in conventional manner, such as byextraction, evaporation and crystallisation. Carbamates of the diallyltartaric diamide can be prepared by reacting the amide with thecorresponding isocyanate. The amide can be dissolved in a suitablesolvent, such as tetrahydrofuran, and be reacted with the isocyanate inthe presence of a catalytic amount of base, e.g.4-dimethylaminopyridine, or a catalyst, e.g. a tin salt. The reaction issuitably conducted by refluxing, and after completion of the reaction,the product is isolated by conventional processing.

Compounds of formula Ib can be prepared from the reaction product of anester of R,R— or S,S— tartaric acid, such as alkyl tartrate, e.g.dimethyl tartrate, and an optically active α-phenylethyl amine. R₂ incompounds of formula Ib suitably is a group RNHCO— or RCO— and then Rmust thus contain an aliphatic double bond, preferably a terminal one.Especially suitable groups R₂ are

Compounds having such groups R₂ can be prepared by known acylationreactions from anhydride and known carbamoylation reactions,respectively. For the preparation of compounds according to formula Ib,where R₂ is a methacrylic acid residue, the diamide is reacted withmethacrylic acid anhydride. The diamide can be solved in a suitablesolvent, such as tetrahydrofuran or chlorinated hydrocarbon, and bereacted with the diamide in the presence of a base, such as4-dimethylaminopyridine at room temperature. For preparing compounds offormula Ib which are carbamates, the same procedure as used forpreparing carbamates of formula Ia can be adopted.

The polymerised derivatives are covalently bonded to the carriermaterial, and the network polymerisate itself can be homo- or copolymersof the indicated tartaric acid derivatives or such polymers that havebeen prepared by hydrosilylation reactions.

The carrier may be an organic or inorganic material. Examples of organiccarriers are styrene-divinyl benzene polymers. Examples of inorganiccarriers are silica, aluminum oxide and zirconium oxide which aremodified with silanes. The polymerised derivatives are bonded to organiccarriers by a C—C bond and to inorganic carriers by an Si—C or Si—O—Sibond. The carrier materials should have a high specific surface andsatisfactory mechanical stability. The surface of the carrier materialshould contain a reactive functional group which either contains aterminal double bond, hydrosilyl group or the silanol group, so that thetartaric acid derivatives can be bonded to the carrier. Examples ofsuitable groups containing a double bond are vinyl, hexenyl, octenyl,acrylic and methacrylic groups. Such groups, as well as hydrosilylgroups, can be bonded to the surface of the carrier material as silicaby known surface-modifying reactions. Structurally, some different,suitable hydrosilyl-modified silica surfaces can be schematicallydefined as follows:

Surfaces I and II have been prepared by modifying a vinyl surface with1,1,3,3-tetramethyldisiloxane and 1,1,4,4-tetramethyldisilylethylene,respectively. Surface III has been prepared by modifying non-derivatisedsilica with 1,3,5,7-tetramethylcyclotetrasiloxane. A variant of surfaceIII can be prepared by using 1,3,5,7-tetravinyltetramethylcyclotetrasiloxane and, by polymerisation thereof, modifyingthe silica surface, which is advantageous to provide optimal coverage ofthe surface.

The optically active adsorbents according to the present invention canbe prepared by network polymerising the tartaric acid derivatives in thepresence of carrier material or by first polymerising the derivativesand then anchoring the network polymer to the carrier material bycovalent bonding.

For certain purposes it might also be suitable to use the tartaric acidderivatives according to formula I as monomers for producing lineartartaric acid polymers. In such cases polymerisation of a tartaric acidderivative containing two terminal unsaturated groups are polymerisedeither by radical polymerisation or by using a bifunctional hydrosilaneor hydrosiloxane.

Network polymerisation of the tartaric acid derivatives, which may existin R,R-form or S,S-form, can be performed by radical polymerisation orby a hydrosilylation polymerisation reaction. The original chirality ofthe derivatives is maintained in the polymerisation. Radicalpolymerisation can be performed by conventional technique. Use is thenmade of free-radical forming initiators such as azo compounds andperoxides, elevated temperatures of from about 50 to 150° C. andreaction times of from about 1 to 24 hours. The polymerisation isconducted in an organic solvent, such as toluene, chloroform or dioxan.

Polymerisation through, hydrosilylation is performed using hydrosilanesor hydrosiloxans. Suitable hydrosilanes and hydrosiloxanes can bedefined by the general formula

wherein R is an alkyl group having 1-4 carbon atoms or H or A mixturethereof, X is (CH₂)_(M) or O and Y is R or the group

—O—Si(R)₃

and n is an integer from 0 to 3000, M is an integer from 0 to 10.Polymerisation through hydrosilylation is known per se and described,e.g., in J. Chromatogr. 1992, 594, 283-290. The basic techniquedisclosed therein can be used for preparing the present chiraladsorbents. The reaction is suitably performed by using a metal complexas catalyst, for example a complex of platinum or rhodium, attemperatures of from about 50 to 180° C., most preferred above 100° C.Solvents that are inert to hydrosilylation are used as polymerisationmedium. Examples of such solvents are toluene, dioxan, mixtures oftoluene and dioxan, chloroform, tetrahydrofuran and xylene. Sincepolymerisation through hydrosilylation is a relatively slow reaction,periods of time from 1 up to about 48 hours may be required.

Radical polymeration is performed in the presence of carrier materialand is most effective when the carrier materials have a surface of theabove-mentioned styryl, methacryloyl, methacrylamide or acrylamide typeand also the tartaric acid derivatives contain these groups. Networkpolymerisation through hydrosilylation is however preferable. Suchpolymerisation shows excellent effectiveness with all of theabove-mentioned types of surfaces. The hydrosilanes will not only beincluded to a varying extent as comonomers in polymerisates of tartaricacid derivatives but also provide bonding to the carrier material.Network polymerisation through hydrosilylation can be performed in thepresence of carrier material or in the absence thereof. In the lattercase, anchorage to the carrier surface is performed by BRINGING thecarrier and the polymer in contact with each other, suitably by addingthe carrier material directly to the solution of the polymer. Freehydrosilyl groups on the network polymer then bind to the modifiedcarrier surface in the presence of catalyst and at the elevatedtemperatures used in polymerisation.

Suitably, use is made of from 1 to 30 μmol of monomeric tartaric acidderivative per m² of carrier surface and of from 1 to 30 μmol ofhydrosilane per m² of carrier surface. Such a high degree of coverage,in μmol per m² of silica, is of course desirable, and the present methodcan yield satisfactory degrees of coverage of at least about 0.70μmol/m².

The present invention also relates to an optically active adsorbentwhich is prepared by network polymerisation through hydrosilylation oftartaric acid derivatives of formula I in the presence of a hydrosilaneor a hydrosiloxane and a carrier material which is surface-modified sothat the surface has one terminal double bond or is a hydrosilyl group,and relates also to an adsorbent prepared by network polymerisationthrough hydrosilylation of tartaric acid derivatives of formula (I) inthe presence of a hydrosilane or a hydrosiloxan, whereupon the carriermaterial, which is surface-modified so that the surface has one reactivefunctional group which either contains a terminal double bond or is ahydrosilyl group, is added to the resulting polymer solution.

The products prepared as above, i.e. the carrier materials coated withpolymerisate, are filtered off and washed with solvent, and are dried.Drying can be conducted at 80-90° C. and suitably under vacuum. The thusprepared chiral adsorbents can thereafter be packed under pressure inchromatography columns in known manner.

The chiral adsorbents according to the present invention have, when usedchromatographically, excellent properties in respect of universality,enantioselectivity and capacity. They can be used for directenantiomeric separation and are well suited for use in HPLC. The chiraladsorbents can be used for both analytical and preparative purposes andfor separation of a very large number of racemates of varying chemicalconsistution, with very good selectivity. Examples of different types ofracemic pharmaceutical substances that can be separated using thepresent chiral adsorbents are benzodiazepinones, benzothiadiazines,dihydropyridines and lactams.

Some of the tartaric acid derivatives used for preparing the chiraladsorbents are new compounds, and the invention also comprises such newcompounds which can be characterised by the formula:

wherein R₁ is a group RNH—, RO—, RR′N— or HO— and R₂ is a group RNHCO—,RCO—, ROCO—, H— or R—, R being an aliphatic hydrocarbon residue havingup to 15 carbon atoms, an aryl group or an aralkyl group or apolyaromatic group and R′ being hydrogen or an alkyl group having up to7 carbon atoms, the derivatives containing at least two groups R₁, or R₂containing an aliphatic unsaturation, R₁, being however not aphenylethyl amino residue when R₂ is H. For the groups R₁, and R₂, R andR′, suitable and preferred groups correspond to what has earlier beenstated for the derivatives of formula I.

Especially preferred compounds are such having the formulae

wherein R₂ is a group RNHCO—, RCO— or R—, where R is as defined above.For compounds of formula IIb, R is however an aliphatic hydrocarbonresidue having up to 15 carbon atoms and containing a double bond.Suitable and preferred compounds otherwise correspond to what hasearlier been stated for the derivatives of formulae Ia and Ib.

The new compounds can be prepared according to the general methods whichhave been described above and which will be described in more detailhereinafter.

The invention will be described more thoroughly in the followingnon-restricting Examples. Figures in parts and per cent are parts byweight and per cent by weight, respectively, unless otherwise stated.

EXAMPLE 1

This Example shows the preparation of chiral tartaric acid derivatives.

1a) Preparation of (+)-N,N′-bis-(α-phenylethyl)-L-tartaric diamide

(+)-Dimethyl-L-tartrate (20.0 g, 0.112 mol) was dissolved in methanol(200 ml), whereupon D(+)-α-phenylethyl amine (135 ml, 1.058 mol) wasadded. The solution was subjected to refluxing for 3 days. The methanolsolution was evaporated to dryness under vacuum. The residue wasdissolved in methylene chloride (2 l). The methylene chloride phase wasextracted with HCl (10%, 3×400 ml), NaHCO₃ solution (5%, 2×200 ml) andwater (1×200 ml). The methylene chloride phase was dried with Na₂SO₄(anhydrous), whereupon the solution was evaporated to dryness undervacuum. The residue was recrystallised in acetonitrile twice (2×200 ml),whereupon white crystals were obtained (20.9 g, yield: 52%).

The product was analysed and the following results were obtained: Purityaccording to HPLC (220 nm):>99%. Melting point: 131-132° C. [α]_(D) ²⁵:+16.0° (MeOH, c=1.05). H'NMR (60 MHz, DMSO-D₆:δ:1.40 (d,6H), 4.27(d,2H), 4.99 (m,2H), 5.64 (d,2H), 7.31 (m,10H), 7.92 (d,2H).

1b) Preparation ofO,O′-dimethacryloyl-(+)-N,N′-bis-(α-phenylethyl-L-tartaric diamide

(+)-N,N′-bis-(α-phenylethyl)-L-tartaric diamide (14.0 g, 39.3 mmol) wasdissolved in dioxan (280 ml) at room temperature. Methacrylic anhydride(12.9 ml, 86.5 mmol) and 4-dimethylaminopyridine (10.6 g, 86.5 mmol)were then added. The solution was left with stirring at room temperaturefor 4 h. The dioxan solution was evaporated to dryness at 30° C. undervacuum. The residue was dissolved in methylene chloride (350 ml). Themethylene chloride phase was extracted with HCl (10%, 3×200 ml), NaHCO₃solution (1×200 ml, 5%) and water (1×200 ml). The methylene chloridephase was dried with Na₂SO₄ (anhydrous), and thereafter evaporated todryness at 30° C. under vacuum. 20.9 g of product was obtained as anoil. This oil was purified by preparative liquid chromatography: Column:5×25 cm with Kromasil®-C18, 16 μm. After this purification, a whitecrystalline product (11.5 g, yield: 60%) was obtained.

The product was analysed and the following results were obtained: Purityaccording to HPLC (220 nm):>99%. Melting point: 129-130° C. [α]_(D) ²⁵:+60.4 g (MeOH, c=1.0). H'NMR (60 MHz, CDCl₃):δ:1.43 (d,6H), 1.92 (S,6H),5.06 (m,2H), 5.70 (m,4H), 6.16 (S,2H), 6.51 (6m,2H), 7.24 (m,10H).

1c) Preparation of O,O′-di-(allyl carbamoyl)-(+)-N,N′-bis-(αphenylethyl)-L-tartaric diamide

(+)-N,N′-bis-(α-phenylethyl)-L-tartaric diamide (10.0 g, 28.0 mmol) wasdissolved in tetrahydrofuran (300 ml). 4-dimethylaminopyridine (7.9 g,64.6 mmol) and allyl isocyanate (11.4 ml, 129 mmol) were then added. Thesolution was subjected to refluxing with stirring for 24 h. The productwhich precipitated in tetrahydrofuran after 24 h was filtered and washedwith tetrahydrofuran and petroleum ether (boiling point 30-40° C.). 12.9g of white crystalline product was obtained. The product wasrecrystallised in dimethyl formamide (30 ml), filtered and washed withtetrahydrofuran. After recrystallisation, 11.0 g of product (yield: 75%)was obtained.

The product was analysed and the following results were obtained: Purityaccording to HPLC (220 nm):>99%. Melting point: 225° C. [α]_(D) ²⁵:+7.6° (DMSO, c=1.02). H'NMR (400 MHz, DMSO-D₆):δ:1.38 (d,6H), 3.61(m,4H), 4.93 (m,2H), 5.04 (d,2H), 5.13 (d,2H), 5.51 (s,2H), 5.75 (m,2H),7.23 (m,10H), 7.37 (t,2H), 8.03 (d,2H).

1d) Preparation of O,O′-di-(3,5-dinitrobenzoyl)-N,N′-diallyl-L-tartaricdiamide

N,N′-diallyl-L-tartaric diamide (14.6 g, 63.95 mmol) was dissolved inpyridine (50 ml). 3,5-Dinitrobenzoyl chloride (30.18 g, 130.9 mmol) wasthen added with ice cooling. The solution was left with stirring for 3 hat room temperature. The pyridine solution was supplied with methylenechloride (1.0 l), whereupon the methylene chloride phase was extractedwith HCL (10%, 3×300 ml), NaHCO₃ (5%, 2×200 ml) and water (1×200 ml).The methylene chloride phase was dried with Na₂SO₄ and evaporated todryness. A yellow-white crystalline residue was obtained. The residuewas recrystallised in dimethyl formamide (70 ml), and a whitecrystalline product was obtained (32.0 g, yield: 81%).

The product was analysed and the following results were obtained: Purityaccording to HPLC (220 nm):>99%. Melting point: 232-233° C. [α]_(D) ²⁵:−75° (DMSO, c=1.02). H'NMR (60 MHz, ⁻DMSO-D₆):δ:3.71 (m,4H), 4.94(m,4H), 5.65 (m,2H), 5.99 (S,2H), 8.85 (d,2H), 9.0 (m,6H).

1e) Preparation ofO,O′-di((R)-α-phenylethyl)-carbamoyl-N,N′-diallyl-L-tartaric diamide

N,N′-diallyl-L-tartaric diamide (4.6 g, 20 mmol) was dissolved in drytetrahydrofuran (100 ml) with stirring. 4 drops of triethylamine werethen added and (+)-phenylethyl isocyanate (6.8 ml, 48 mmol) was addeddropwise. When the total amount of the isocyanate had been added, thereaction mixture was subjected to refluxing for 36 h. The reactionsolution was evaporated and the residue was dissolved in methylenechloride and extracted with diluted H₂SO₄, NaHCO₃ solution and H₂O. Theorganic phase was dried with MgSO₄, evaporated and the residue wasrecrystallised from a dimethyl formamide/methanol mixture. White needleswere obtained, and the yield was 54%.

The product was analysed and the following results were obtained:Melting point: 268.6-269.7° C. [α]_(D) ²⁵: +20° (DMSO, c=1) H'NMR (400MHz, DMSO-D₆):δ:1.36 (d,6H), 3.64 (m,4H), 4.62 (m,2H), 4.92 (d,2H), 5.05(d,2H), 5.34 (S,2H), 5.68 (m,2H), 7.29 (m,10H), 7.69 (d,2H), 7.94(m,2H).

1f) Preparation of O,O′-dibenzoyl-N,N′-diallyl-L-tartaric diamide

N,N′-diallyl-L-tartaric diamide (1 g) was dissolved in pyridine (4 ml),and the solution was left with stirring at about 5° C. Benzoyl chloride(1.26 g) was added dropwise. The reaction mixture was thereafter leftwith stirring for about 1 h at room temperature, whereupon methylenechloride (50 ml) was added. The organic phase was extracted with 1 MH₂SO₄, water, saturated NaHCO₃ solution and water. The organic phase wasdried over Na₂SO₄. Methylene chloride was evaporated and the residue wasrecrystallised from a mixture of acetone and hexane.

The product was analysed and the following results were obtained:Melting point: 200-201° C. [α]_(D) ²⁰: −120°±2° (c=0.5 in acetone) H'NMR(60 MHz, DMSO-D₆):δ:3.68 (4H,m), 4.92 (4H,m), 5.58 (2H,m), 5.84 (2H,s),7.64 (6H,m), 8.08 (4H,m), 8.64 (2H,t).

1 g) Preparation of O,O′-diphenylcarbamoyl-N,N′-diallyl-L-tartaricdiamide

N,N′-diallyl-L-tartaric diamide (4.6 g, 20 mmol) was suspended in 150 mlof dry CHCl₃. 4 drops of triethyl amine were added with stirring. Themixture was subjected to refluxing until the diamide had been dissolved.Phenylisocyanate (5.2 ml, 48 mmol) was thereafter added dropwise to themixture. The reaction mixture was subjected to refluxing with stirringfor 12 h. The cooled solution was extracted with 50 ml 1M H₂SO₄, 50 mlsaturated NaHCO₃ solution and 2×50 ml H₂O. The organic phase was driedwith MgSO₄, evaporated and the residue was recrystallised from a mixtureof tetrahydrofuran and methanol. White needles were obtained, and theyield was 82%.

The product was analysed and the following results were obtained:Melting point: 253.2-255° C., [α]_(D) ²⁰: −83.4°, (c=0.5 in DMSO).[α]_(D) ²⁰: −60.8° (c=1.0 in THF). H'NMR (60 MHz, DMSO-D₆) δ:3.72(4H,m), 5.04 (4H,m), 5.62 (2H,s), 5.76 (2H,m), 6.92 (2H,m), 7.00 (2H,m),7.28 (4H,m), 7.46 (4H,m), 8.30 (2H,t).

1h) Preparation of O,O′-dinaphthylcarbamoyl-N,N′-diallyl-L-tartaricdiamide

N,N′-diallyl-L-tartaric diamide (0.46 g, 2 mmol) was dissolved in 200 mlof dry tetrahydrofuran. 1 drop of triethyl amine was added. 1-Naphthylisocyanate (0.69 ml, 4.8 mmol) was thereafter added dropwise. Thereaction mixture was subjected to refluxing for 36 h. A thick red-whiteprecipitation was obtained and filtered off, washed with 50 ml ofmethanol and recrystallised from a mixture of dimethyl formamide andmethanol. White needles were obtained, and the yield was 33%.

The product was analysed and the following results were obtained:[α]_(D) ²⁵: −24° (DMSO, c=1). H'NMR (400 MHz, DMSO-D₆):δ:3.82 (m,4H),5.03 (d,2H), 5.21 (d,2H), 5.65 (s,2H), 5.82 (m,2H), 7.54 (m,8H), 7.77(m,2H), 7.92 (m,2H), 8.07 (m,2H), 8.36 (t,2H), 9.63 (m,2H),

EXAMPLE 2

This Example illustrates surface modification of an original carriermaterial for introduction of functional groups.

I. Surface modification for introducing a functional group containing aterminal double bond

10 g of Kromasil®, a silica material produced by Eka Nobel AB, Swedenand having an average particle size of 5 μm, an area of 256 m²/g and anaverage pore diameter of 150 Å, was slurried in 50 ml of methylenechloride. Monochlorosilane (8 μmol/m² SiO₂) and pyridine (8 μmol/m²)were then added. The solution was subjected to refluxing in a nitrogenatmosphere with stirring for 24 h. The solution was thereafter filteredand the derivatised silica was washed with methylene chloride,tetrahydrofuran and methanol. The surface-modified silica material wasthen dried at 80-90° C. for 24 h. The following differentmonochlorosilanes were used for surface modification as above:

Dimethylvinyl chlorosilane

Trivinyl chlorosilane

m,p-styrylethyldimethyl chlorosilane

6-hex-1-enyldimethyl chlorosilane

7-oct-1-enyldimethyl chlorosilane

3-methacryloxy propyldimethyl chlorosilane

Another method for introducing of vinyl groups on the surface was alsoused. A vinyl-containing cyclic tetrasiloxane was used for modifying thesame silica material as above. The silica material (10 g) was slurriedin 50 ml of toluene. Tetravinyl tetramethyl-cyclotetrasiloxane (8.0μmol/m² SiO₂) and trifluoromethane sulphonic acid (10 mg, catalyticamount) were then added. The solution was subjected to refluxing undernitrogen atmosphere with stirring for 18 h. The solution was thereafterfiltered and the derivatised silica was washed with methylene chloride,tetrahydrofuran and methanol. The surface-modified silica material, withpolymeric vinyl surface, was thereafter dried at 80-90° C. for 24 h.

II. Surface modification for introducing a hydrosilyl group

IIa) 5 g of the silica material Kromasil®, which had beensurface-modified with vinyldimethyl chlorosilane, was suspended in 25 mlof chloroform, whereupon an H₂PtCl₆ solution (0.15 ml, concentration: 55mg/ml isopropanol) was added. 1,1,3,3-tetramethyldisiloxane (8.0 μmol/m²SiO₂) was thereafter added. The solution was subjected to refluxing innitrogen atmosphere for 18 h. The derivatised silica was washed andthereafter dried as earlier. This method yielded a coverage degree withrespect to hydrosilane of 1.72 μmol/m² SiO₂. δC:2.0%.

IIb) Surface modification was performed in the same way as according toIIa, but with the difference that toluene was used instead of chloroformand the silane reagent was 1,1,4,4-tetramethyldisilyl ethylene. Thecoverage degree with respect to hydrosilane was 1.64 μmol and δC:2.35%.

IIc) In this mode of execution, the base material was non-modifiedKromasil®. 5.0 g of the silica material was slurried in 25 ml oftoluene. 1,3,5,7-Tetramethyl cyclotetrasiloxane (8.0 μmol/m² SiO₂=2.50ml) and trifluoromethane sulphonic acid (10 mg) were then added. Thesolution was subjected to refluxing in nitrogen atmosphere for 18 h. Thecoverage degree was 8.80 μmol/m² SiO₂, δC:2.35%.

EXAMPLE 3

The following Example illustrates polymerisation, by hydrosilylationpolymerisation, of tartaric acid derivatives on silica carriers. Thesilica material used was Kromasil® in all cases.

a) 5.0 g of silica material, modified with vinyl, was suspended in 30 mlof a 1:1 mixture of toluene and dioxan, whereupon an H₂PtCl₆ solution(0.10 ml, concentration: 60 mg/ml isopropanol) was added.Polymethylhydrosiloxan (Mw 360-420, 2.8 ml) was thereafter added. Thesolution was subjected to refluxing under nitrogen atmosphere for 2 h.O,O′-dibenzoyl-N,N′-diallyl-L-tartaric diamide (10 mmol) was thereafterADDED. The solution was subjected to refluxing for another 18 h innitrogen atmosphere. The thus treated silica material was filtered offand washed with dioxan, acetonitrile and tetrahydrofuran. The materialwas thereafter dried at 90° C. under vacuum for 24 h.

An elementary analysis gave in per cent by weight: C:16.15% (δC:11.5%),N:0.38% (0.56 μmol/m² (with respect to dibenzoyl diallyl tartaricdiamide).

b) O,O′-(1-naphtoyl) -N,N′-diallyl-L-tartaric diamide (8.9 mmol, 4.79 g)was dissolved in toluene:dioxane (1:1, 45 ml) whereupon an H₂PtCl₆solution (0.15 ml, concentration: 55 mg/ml isopropanol) as well astertrakis (dimethyl siloxy) SILANE (6.7 mmol, 2.50 ml) was added. Thesolution was subjected to refluxing in nitrogen atmosphere for 24 h.Thereafter 5.0 G of carrier material (Kromasil®, modified with vinyl wasadded to the solution. The reaction was left further 24 hours withreflux under nitrogen. The product was filtered and washed withtetrahydrofurane, toluene and dichloromethane and dried at 90° C. undervacuum for 24 h. An anaylsis of carbon and nitrogen content gave gave9.1 and 0.30 respectively, in per cent by weight, which corresponds to0.44 μmolm2 SiO₂.

c) 5.0 g of carrier material (Kromasil®, modified with vinyl), wassuspended in 45 ml of tetrahydrofuran. H₂PtCl₆ (0.15 ml, concentration:55 mg/ml isopropanoi), tertrakis (dimethyl siloxy) silane (7.5 mmol, 2.8ml) and O,O′-diphenylcarbamoyl-N,N′-diallyl-L-tartaric diamide (10.25μmol, 4.8 g) were thereafter added. The solution was placed in anautoclave. The reaction was left at 125° C. during 18 hours undernitrogen atmosphere. The product was filtered off and washed withdimethylformamide and tetrahydrofuran. An anaylsis of carbon andnitrogen content gave 12.1 and 0.95 respectively, in per cent by weight,which corresponds to 0.72 μmol/m² SiO₂.

d) O,O′-dibenzoyl-N,N′-diallyl-L-tartaric diamide (10.0 mmol, 4.36 g)was dissolved in toluene:dioxan (1:1, 30 ml), whereupon a solution ofH₂PtCl₆ (0.15 ml, concentration: 55 mg/ml isopropanol) was added.Tetrakis(dimethyl siloxy)silane (7.5 mmol, 2.8 ml) was thereafter added.The solution was subjected to refluxing in nitrogen atmosphere for 24 h.5.0 g of carrier material (Kromasil® modified with vinyl) was thereafteradded to the solution. The reaction was allowed to proceed for another24 h with refluxing in nitrogen atmosphere. The product was filtered andwashed with tetrahydrofuran, toluene and dichloromethane and dried for24 h at 90° C. under vacuum. An analysis of the carbon content and thenitrogen content showed 11.85% by weight and 0.50% by weight,respectively, corresponding to 0.76 μmol/m² SiO₂.

EXAMPLE 4

This Example illustrates chromatography using a chiral stationary phaseaccording to the invention.

Silica material with network polymerised tartaric acid derivativeaccording to Example 3D) was packed with conventional slurry-packingtechnique in a stainless steel HPLC column (4.6×250 mm).Enantioselectivity for a number of test racemates was examined. The testracemates were pharmaceutical preparations which are indicated in thefollowing Table under their registered trademarks and with an indicationof structural type or chemical or generic name. The enantioselectivityis expressed as α, which is a measure of the ratio between the capacityfactors of the enantiomers. k′₁=(t₁−t₀)/t₀; k′₂=(t₂−t₀)/t₀; α=k′₂/k′₁wherein t₁, and t₂=retention times for enantiomers as first and as lasteluted, respectively, t₀=retention time for unretarded compound, k′₁ andk′₂ =capacity factors for enantiomers as first and as last eluted,respectively.

Mobile Test racemate Structural type α k′₁ phase Oxazepam Benzodiaz-1.13 3.71 A Lopirazepam epinones 1.59 4.73 A BendroflumethiazideBenzothia- 1.22 7.3  A Paraflutizide diazines 1.19 12.68  A FelodipineDihydro- 1.0  3.71 B 152/80* pyridines 1.09 5.80 A Ibuprofen Profens1.32 2.27 F Ketoprofen 1.12 5.38 F Baclofenlactam Lactam 1.13 2.82 BHexobarbital Barbiturate 1.04 2.98 E Chlormezanone 1.13 6.39 BChlorthalidone 1.50 3.83 B Warfarin 1.13 5.13 D 1,1′-Bi(2-naphthol) 1.262.29 B 1-(9-Anthryl)-2,2,2- trifluoroethanol 1.10 4.06 C 1-Phenylethanol1.08 0.86 C Benzylmandelate 1.16 1.21 I 1-(9-fluorenyl)ethanol 1.05 2.32I Metoprolo β-amino 1.08 2.78 G Propranolol alcohols 1.03 6.68 HClenbuterol 1.32 0.57 K

The mobile phases indicated by letters were:

A=hexane:isopropanol (90/10)

B=hexane:isopropanol (95/5)

C=hexane:isopropanol (98/2)

D=hexane:isopropanol (99/1)

E=hexane:dioxan (95/5)

F=hexane:isopropyl alcohol:trifluoroacetic acid (99.4/0.5/0.1)

G=hexane:isopropyl alcohol:trifluoroacetic acid (94.9/5/0.1)

H=hexane:isopropyl alcohol:trifluoroacetic acid (96.9/3/0.1)

I=hexane:isopropyl alcohol (99.5/0.5)

K=methylene chloride:ethanol:trifluoroacetic acid (97.9/2/0.1)

The indicated mixing ratios are in per cent by volume.

As appears from the results indicated in the Table, these chiralstationary phases which are based on network polymers of tartaric acidderivatives exhibit a general enantioselectivity for most types ofpharmaceutical substances.

We claim:
 1. An optically active adsorbent comprising an opticallyactive network polymer covalently bonded to a carrier.
 2. The opticallyactive adsorbent according to claim 1, wherein the optically activenetwork polymer comprises optically active derivatives of dicarboxylicacids, diamines, diols or hydroxy acids.
 3. The optically activeadsorbent according to claim 2, wherein each functional group of theoptically active dicarboxylic acid derivatives, the diamines and thediols comprise at least one aliphatic carbon chain with up to 15 carbonatoms and at least one terminal unsaturation.
 4. The optically activeadsorbent according to claim 2, wherein the hydroxy acid is a networkpolymerized tartaric acid derivative of the general formula:

wherein R₁ is a group RNH—, RO—, RR′N or HO— and R₂ is a group RNHCO—,RCO—, ROCO—, R— or H—, R being an aliphatic hydrocarbon residue havingup to 15 carbon atoms, an aryl group, an aralkyl group, a naphthyl groupor an anthryl group and R′ being hydrogen or an alkyl group having up to7 carbon atoms, the derivatives containing at least two groups R₁ or R₂containing an aliphatic unsaturation, and the network polymerizedtartaric acid derivatives being covalently bonded to the surface of asolid carrier material.
 5. An adsorbent according to claim 4, whereinthe tartaric acid derivatives have the general formula

wherein R₂ is a group RNHCO—, RCO— or H and R is an aliphatichydrocarbon residue having up to 15 carbon atoms, an aryl group, anaralkyl group, a naphthyl group or an anthryl group.
 6. An adsorbentaccording to claim 5, wherein R is a substituted or unsubstituted arylgroup, an aralkyl group, a naphthyl group or an anthryl group.
 7. Anadsorbent according to claim 6, wherein the tartaric acid derivativeshave the general formula

wherein R₂ is a group RNHCO— or RCO—, R being an aliphatic hydrocarbonresidue having up to 15 carbon atoms and containing an aliphatic doublebond.
 8. An adsorbent according to claim 7, wherein R₂ is the group


9. An adsorbent according to claim 1, wherein the solid carrier materialis silica.
 10. A method for preparing an optically active adsorbent,wherein tartaric acid derivatives as defined in claim 4 are networkpolymerized by radical polymerization or through hydrosilylation in thepresence of solid carrier material.
 11. A method according to claim 10,wherein the derivatives are polymerized through hydrosilylation in thepresence of hydrosilanes or hydrosiloxanes of the general formula

wherein ⁻R is an alkyl group having from 1 to 4 carbon atoms or H or amixture thereof, X is (CH₂)_(m) or O, and Y is R or the group —O—Si(R)₃,and n is an integer from 0 to 3000, m is an integer from 1 to
 10. 12. Anoptically active adsorbent obtainable by radical polymerization orpolymerization through hydrosilylation of tartaric acid derivatives asdefined in claim 4 in the presence of a solid carrier material.
 13. Anoptically active adsorbent according to claim 12, obtainable byhydrosilylation polymerization.
 14. A method for preparing an opticallyactive adsorbent, wherein tartaric acid derivatives as defined in claim4 are network polymerized through hydrosilylation in the presence of ahydrosilane or hydrosiloxan of the general formula

wherein R is an alkyl group having from 1 to 4 carbon atoms or H or amixture thereof, X is (CH₂)_(m) or O, and Y is R or the group —O—Si(R)₃,and n is an integer from 0 to 3000, m is an integer from 1 to 10, andthe resulting network polymer is thereafter anchored to the surface ofsolid carrier material in the presence of a catalyst and atpolymerization temperature.
 15. An optically active adsorbent madeaccording to claim 14, wherein the tartaric acid derivative has thegeneral formula

wherein R₂ is a group RNHCO—, RCO— or H and R is an aliphatichydrocarbon residue having up to 15 carbon atoms, an aryl group, anaralkyl group, a naphthyl group or an anthryl group.
 16. An opticallyactive adsorbent made according to claim 14, wherein the tartaric acidderivative has the general formula

wherein R₂ is a group RNCO— or RCO—, R being an aliphatic hydrocarbonresidue having up to 15 carbon atoms containing an aliphatic doublebond.
 17. An optically active adsorbent obtaining by networkpolymerization through hydrosilylation of a tartaric acid derivative asdefined in claim 4 in the presence of a hydrosilane or a hydrosiloxaneof the general formula

wherein R is an alkyl group having from 1 to 4 carbon atoms or H or amixture thereof, X is (CH₂)_(m) or O, and Y is R or the group —O—Si(R)₃,and n is an integer from 0 to 3000, m is an integer from 1 to 10,followed by anchoring the obtained network polymer to the surface of asolid carrier material in the presence of a catalyst and atpolymerization temperature.
 18. A network polymer obtainable bypolymerization through hydrosilylation of a tartaric acid derivative asdefined in claim 4 in the presence of a hydrosilane or hydrosiloxanehaving the general formula

wherein R is an alkyl group having from 1 to 4 carbon atoms or H or amixture thereof, X is (CH₂)_(m) or O, and Y is R or the group —O—Si(R)₃,and n is an integer from 0 to 3000, m is an integer from 1 to
 10. 19. Amethod for chromatographic separation of racemic mixtures inenantiomers, wherein said racemic mixture is chromatographed on anoptically active adsorbent as defined in claim
 1. 20. The opticallyactive adsorbent according to claim 2, wherein said optically activenetwork polymer comprises optically active derivatives of compoundsselected from the group consisting of D- or L- tartaric acid, (1R,2R)-(−)-1,2 diamino cyclohexan, (+)-2,2′-diamino binaphthyl-(1,1′),(1R,2R)-(−)-1,2-cyclohexan diol,(+)-(2R,3R)-1,4-dimethoxy-2,3-butandiol, D-(−)-citramalic acid andD-(+)-malic acid.